1. Field of the Invention
The present invention relates to blood sampling and, more particularly, to the ultrasonic measurement of hematocrit and/or hemoglobin concentration of a small blood sample.
2. Discussion of the Background
Physicians routinely test blood parameters as part of the diagnostic process. The complete blood count (CBC) is the most common of these tests. A CBC measures the status of important features of the blood, including the following: mean corpuscular hemoglobin, which is also called MCH; mean corpuscular hemoglobin concentration, which is also called MCHC; mean corpuscular volume, also called MCV; number of platelets; number of red blood cells (RBCs); number of white blood cells (WBCs); percentage of blood volume composed of red cells, called hematocrit (HCT); and total concentration of hemoglobin in the blood, also called HGB. Physicians use the results to assess the quantity and the condition of the blood's cellular components. For example, the CBC hemoglobin concentration (or HGB, typically stated in g/dl) describes the oxygen-carrying capacity of the red blood cells because HGB is the protein that the body uses to transport oxygen. The hematocrit or “HCT” (measured in a % concentration) is defined as the portion of the total volume of blood occupied by red blood cells. This volume fraction may be expressed as a decimal (e.g., liter/liter) or as a percentage (e.g., liter/liter×100%). HCT measurements typically provide the same information to the physician as the hemoglobin concentration (HGB)—the oxygen carrying capacity of the blood—because under normal physiological conditions almost all of the blood's hemoglobin is in the red blood cells. The Mean Corpuscular Volume (MCV) is the average of the red blood cell volume. The Red Blood Cell Count (RBC) is an expression of the number of red blood cells per unit volume of blood, typically, cells per microliter (□l). Mean Cellular Hemoglobin (CH) is the average mass of hemoglobin that can be found in each red blood cell. In contrast, Mean Cellular Hemoglobin Concentration (MCHC) is the average concentration (instead of mass) of hemoglobin in red blood cells. The concentration of hemoglobin in a blood cell is simply the mass of hemoglobin divided by the volume it occupies: MCHC=MCH/MCV, meaning that MCHC can be calculated from the MCH and MCV instead of being independently measured. Among the other components of blood that are characterized in a complete blood count include white blood cells and platelets. Whole blood is defined as blood that includes red blood cells, white blood cells, platelets, and all the normal components of blood.
These blood properties, in particular HCT and/or HGB, can be used to diagnose anemia, acute blood loss, dehydration, and scores of other conditions. Physicians routinely monitor HCT both acutely and chronically and may act on changes of as little as two percent (2%) of the measured value.
In the hospital environment, the blood lab routinely performs complete blood counts. Blood samples are drawn into vials and delivered to the central blood lab where an automated system performs the testing. The results are relatively accurate, but not immediately available (typically requires 10 minutes to 1 hour). Alternatively, there are a few handheld blood parameter devices that provide measurements of HCT or HGB at the point of care, but the intrusiveness of the measurement and the relative inaccuracy inherent in these devices limits their diagnostic value.
In the emergency medical environment, there is currently no method to measure HCT or HGB in the field to the same accuracy as the automated blood lab systems. The existing handheld devices noted above are difficult to use or are not sufficiently accurate. Patients requiring a hematocrit measurement, such as victims of trauma or disaster, must await transport to a hospital or clinic with a blood lab before this information can be accurately measured. If accurate results were available in the field, it would improve the ability of medical personnel to triage patients and speed the delivery of appropriate medical care when the patient arrived at the hospital.
In the field, it can be difficult to assess the extent to which an injured patient has bled internally. A patient's HCT decreases with blood loss. Consequently, successive HCT measurements provide a valuable indication of the degree of blood loss. In cases where the emergency medical personnel are overwhelmed by the number of injured, a device which quickly and accurately measures the HCT of those in need of medical care would greatly improve the ability of the emergency medical personnel to focus their attention on critical cases. Thus, the public emergency medical industry and the military have a significant need for a device and method capable of measuring HCT quickly, accurately and at point-of-care.
Private practice physicians who need accurate measurements of HCT are currently limited to sending blood samples to a contract blood lab, or performing slow, imprecise manual techniques that are subject to human error such as spun hematocrit or microscopic inspection.
Four methods are currently available to measure HCT:                centrifuge,        cell count,        optical characteristics, and        electrical characteristics.        
The centrifuge method is the most basic measurement technique. These centrifuges are not portable. To measure HCT, a blood sample is drawn and spun in a centrifuge (e.g. READACRIT®) for a fixed duration (typically five to thirty minutes, depending on protocol). The spin separates the blood sample into three layers. The top layer is the plasmas made up primarily of water and dissolved solids. The next layer is the thin buffy coat, made up of white blood cells, plasma proteins, and platelets. The bottom layer contains closely packed red blood cells. A technician reads the volume fraction directly using a scale. Spun hematocrit accuracy can be affected by user error in reading the scale, plasma entrapped in the red blood cell column, and distortion of red blood cell size. Typically, the resulting accuracy of a spun hematocrit performed to protocol is 2 to 5% of the measured value. This accuracy, as with all other accuracies in this report, is reported as the 95% confidence interval around the mean.
Cell counting is the most direct of the measurement techniques. The blood sample is diluted to a known ratio and individual cells are counted either manually or automatically. Manual cell counting techniques are tedious and proper preparation of the sample depends on the skill of the operator. Automated cell counters (e.g. COULTER@ GEN STM System) typically offer 1-minute sample turnaround, claim accuracies to 2.0-3.5% of the measured value, and reduce tedium and operator dependence. As a practical matter, the turnaround time at the point of care is typically 30 minutes to 12 hours, because blood samples must be transported from the patient to the centrally located lab, processed, and the results must be reported back to the point of care. Furthermore, automated systems are typically expensive and are not portable.
The optical measurement technique is relatively new. Devices employing this technique measure the amount of light transmitted through, or reflected from, flowing blood. These devices (e.g. 3M® CDITM System 500) are designed for use during cardiac surgery, require a blood circuit, and are not portable.
HemoCue®, is an example of a handheld device that photometrically measures the blood hemoglobin concentration. Such portable photometric devices have a 1-minute cycle time, but the accuracy is typically around 3%. A portable device with greater accuracy would be valuable because physicians make decisions based on changes as small as 1-2% of the reading.
Electrical conductivity is currently used to measure a variety of blood parameters, including hematocrit. The i-STAT® system, for example, measures the conductivity of a blood sample, corrects for ion concentrations, assumes normal white blood cell and protein levels and then calculates and reports hematocrit. While instruments that use electrical conductivity are portable, the accuracy of a typical conductivity-based hematocrit reading is 6%, which substantially reduces the clinical value.
In the field of blood ultrasonics, much investigation has focused on analyzing ultrasonic backscatter in devices that measure blood flow velocity using the Doppler effect. In contrast, there is much less research on the relationship between speed of sound and hematocrit.
For example, the following references are hereby incorporated by reference:
Edwin L. Carstensen, Kam Li, and Herman P. Schwan, “Determination of the Acoustic Properties of Blood and its Components,” The Journal of the Acoustical Society of America Volume 23, Number 2, Pages 286-289 (1953).
Edwin L. Carstensen and Herman P. Schwan, “Absorption of Sound Arising from the Presence of Intact Cells in Blood,” The Journal of the Acoustical Society of America Volume 31, Number 2, Pages 185-189 (1959).
Rubens A. Sigelmann and John M. Reid, “Analysis and Measurement of Ultrasound Backscattering from an Ensemble of Scatterers Excited by Sine-Wave Bursts,” The Journal of the Acoustical Society of America Volume 53, Number 5, Pages 1351-1355 (1973).
KoPing K. Shung, Rubens A. Sigelmann, and John M. Reid, “Scattering of Ultrasound by Blood,” IEEE Transactions on Biomedical Engineering Volume BME-23, No. 6, Pages 460-467 (1976).
Stephen E. Borders, Arnost Fronek, W. Scott Kemper and Dean Franklin, “Ultrasonic Energy Backscattered from Blood,” Annals of Biomedical Engineering, Volume 6, pages 83-92 (1978).
S. Xu and H. Ermert, “Models for Describing the Scattering of Ultrasound in Blood,” Biomed. Technik, Volume 42 (5), Pages 123-131 (1997).
S. A. Gross, R. L. Johnston, and F. Dunn, “Comprehensive Compilation of Empirical Ultrasonic Properties of Mammalian Tissues” J. Acoust. Soc. Amer., Vol. 64, Pages 423-457, 1987.
Larry Y. L. Mo and Richard S. C. Cobbold, “A Stochastic Model of the Backscattered Doppler Ultrasound from Blood,” IEEE Transactions on Biomedical Engineering, Volume BME-33, No. 1, Pages 20-27 (1986).
I. Y. Kuo and K. K. Shung, “High Frequency Ultrasonic Backscatter from Erythrocyte Suspension,” IEEE Transactions on Biomedical Engineering, Volume 41, No. 1, Pages 29-33 (1994).
Daniel Schneditz, Thomas Kenner, Helmut Heimel, and Hans Stabinger, “A sound-speed sensor for the measurement of total protein concentration in disposable, blood-perfused tubes,” J. Acoust. Soc. Am., Vol. 86, No. 6, Pages 2073-2080 (1989).
K. Kirk Shung, Guy Cloutier, and Chee C. Lim, “The Effects of Hermatocrit, Shear Rate, and Turbulence on Ultrasonic Doppler,” IEEE Transactions on Biomedical Engineering, Volume 39, No. 5, Pages 462-489 (1992).
These studies are useful for understanding the interaction between ultrasound and blood. Also, many researchers have explored the ultrasonic characteristics of blood for the purpose of better understanding how these characteristics enable or interfere with imaging and sonography devices. However, they suggest no practical implementation for the ultrasonic measurement of hematocrit (HCT) or hemoglobin (HGB) concentrations of a small blood sample using a field-portable device.
Schneditz et al (U.S. Pat. No. 5,830,365) built a sound-speed sensor and evaluated it as a method for measuring total protein concentration in a tube of flowing blood. The device is intended to track fluid shifts in a patients blood as they are on a hemodialysis machine. These fluid shifts would manifest themselves as a change in total protein concentration. Schneditz investigated the correlation between total protein concentration and speed of sound in order to detect these fluid shifts. He implemented a speed of sound measurement by measuring time of flight along a single direct path. A disadvantage of the Schneditz device is that it only works with continuously circulating blood from the patient and back into the patient (such as, for example, in an inline hemodialysis apparatuses), where the blood is continuously flowing in order to avoid settling of the blood cells from; the plasma, which would cause inaccurate readings. Another disadvantage is that it requires a large volume (60 mL) of blood circulating through tubing from a thermostatted 500 mL bath, and it requires calibration with reference fluids whose speed of sound was known accurately. Again, these considerations limit the effectiveness for rapid deployment in the field. Moreover, the Schneditz device has been implemented on porcine blood (pig blood) with the white blood cells artificially removed (along with any other blood components in the white blood cell layer). The absence of white blood cells and the physical differences between porcine blood and human blood may significantly alter the ultrasonic response of the blood and therefore the Schneditz et al correlations and methods may not apply to whole or human blood. What is needed is an approach that can be implemented in a hand-held device, using only 1 drop of blood, and yet still provide high-accuracy measurement of hematocrit and/or hemoglobin concentration. None of Schneditz nor any of the foregoing or other known apparatus or methods solve the combined problems of speed, accuracy, and portability in hematocrit or hemoglobin concentration measurement. Moreover, in order to sonically measure HCT concentration with accuracy, it is also necessary to either measure or control the temperature of the blood sample. Conventional methods for controlling temperature, including thermostat-controlled baths are cumbersome and impractical. Other methods for measuring, such as directly contacting the blood with a temperature probe, lead to cleaning and contamination complications. As such, there also remains a need for effecting an accurate and efficient temperature measurement of a small blood sample in a field-portable device.
The present invention accomplishes all four goals, namely, speed, portability, proficient temperature measurement, and high-accuracy measurement of hematocrit and/or hemoglobin concentration, simultaneously in a field-capable device.